Interferon-gamma (IFN-gamma) is a T-cell and natural killer cell product with diverse physiological functions. This cytokine is a potent immune modulator and a major activator of macrophages and other immune cells. IFN-gamma also has the ability to inhibit the growth of cells, in some cases inducing apoptosis. Recognition of its anti-proliferative properties and its ability to stimulate the immune system has led to the investigation of IFN-gamma's therapeutic activity in a number of malignant conditions, and in particular ovarian cancer. In vitro and in vivo studies, IFN-gamma has been shown to be directly toxic to ovarian cancer cells and to stimulate the body's immune system to enhance the removal of cancer cells. IFN-gamma has a short half-life after subcutaneous administration (25-35 min) that necessitates frequent administration and reduces potential efficacy. We propose to create novel polymer modified IFN-gamma proteins that can be administered less frequently, but with greater potency in vivo, than existing IFN-gamma products. During Phase I we will identify sites in IFN-gamma that can be modified without affecting the protein's in vitro and in vivo bioactivity. During Phase II, we will develop manufacturing processes to produce sufficient quantities of the modified IFN-gamma proteins for testing in additional animal PK and tumor models. The improved characteristics of the novel IFN-gamma proteins should reduce the amount of IFN-gamma required per patient, enhance efficacy, reduce toxicity, improve patient compliance and quality of life and result in considerable cost savings to patients and healthcare providers. IFN-gamma is a member of a large family of structurally related growth factors and cytokines. Information gained from these studies will aid in creating long-acting versions of other members of this gene family for use in treating cancer, infectious disease and hematopoietic disorders.